Aim 1. Establish interventions for early disease in the transgenic rhodopsin P347L (TgP347L) rabbit, a model of human retinitis pigmentosa (RP). TgP347L rabbits (1-30 month old) will receive subretinal injections of shRNA-adeno-associated virus (AAV) to suppress mutant opsin production. Analyses include eye imaging, electroretinograms, visual evoked po- tentials, behavior, immunocytochemistry, Western blots, automated transmission electron micro- scope (ATEM) imaging, and electrophysiology by whole cell and multielectrode arrays. Significance. This is a test of early intervention for human RP in large-eye animal model. Aim 2. Establish optogenetic interventions for late disease in RP. TgP347L rabbits >12mos of age will receive (1) subretinal injections of Channelrhodopsin2 (ChR2)-AAV targeting bipolar cells (BCs) or AII amacrine cell (ACs). Analyses will follow those established in Aim 1. Significance. This is a test of late intervention for human RP in a large-eye animal model. Aim 3. Build pathoconnectomes for early and late stage TgP347L rabbit BCs and AII cells. BCs are known to undergo severe rewiring and reprogramming in RP, but the nature of retargeting is completely unknown. The extent of AII cell remodeling is similarly unknown. Methods. ATEM imaging will be used to characterize remodeling networks. Significance. This is the first attempt to quantitatively define rewiring in any neural system in retina or brain and has profound implications for all neurodegenerative disorders. Aim 4. Evaluate retinoic acid and retinoid receptor-based interventions to attenuate corruptive remodeling and reprogramming. TgP347L rabbits will be treated with retinoid X receptor and- tagonists to block pathologic neuritogenesis. Analysis includes ATEM imaging and molecular profiling as in Aim 1. Significance. This is a test of a potential clinical intervention for remodeling RP in a large-eye animal model. PUBLIC HEALTH RELEVANCE: New RNA inhibition and optogenetics interventions offer potential cures for retinitis pigmentosa (RP), even in the presence neuronal remodeling that impedes other therapies. Discovery of the mechanisms remodeling are facilitating anti-remodeling drug testing that may enhance the effectiveness of gene therapies.